Catching a metaphor on the fly: ‘Greenfield genome design’

A week ago, something interesting washed up in my twitter stream, something a metaphor collector like me had to pick up and inspect.

Andrew Hanson, an expert in metabolic engineering working at the University Florida, tweeted: “Excellent short 2016 piece from @claudiaevickers on #synbio platforms & the future of the microbial cell factory industry. Coins term ‘greenfield genome design’ – accurate, evocative, and deserves use!” Claudia Vickers, a synthetic biologist working, amongst others, at the University of Queensland, replied (using another, more well-established metaphor): “Thanks @ADHansonLab, didn’t realize I coined a new term….’greenfield genome design’, the holy grail!”

They didn’t use the word metaphor, but a metaphor is surely what they were talking about.

I looked at the article mentioned in Hanson’s tweet. It’s entitled “Bespoke design of whole-cell microbial machines” (Microbial Biotechnology, 2016). That sounded interesting, especially in terms of the type of work we are doing here at the Synthetic Biology Research Centre. I became curious.

I read the article and specifically at the passage in which the metaphor first occurred, but I wasn’t altogether certain I understood the metaphor. So, I tweeted back and asked: “What does ‘greenfield’ mean in this context? (sorry I am not a microbiologist)” Claudia Vickers kindly replied! She said: “It’s a land development/engineering term. A greenfield site is one that hasn’t been developed before, a clean slate. I used it in this context to imply a bottom-up process unencumbered by prior evolved genetic constraints, no need to demolish/redevelop”.

Andrew Hanson then chipped in by saying: “This was creative and deadly accurate use of metaphor – which is pretty unusual in science and thus worth celebrating!”

So I had a bit more of a think, as a rather naïve non-microbiologist who is interested in metaphors used in synthetic biology, especially since the creation of an artificial cell nicknamed ‘Synthia’ by Craig Venter in 2010.

Metaphor in context

Let’s first have a look at the passage in which the metaphor was created:

“The minimal genome developed recently by the J. Craig Venter Institute (JCVI; (Hutchison et al., 2016) is the smallest known genome capable of sustaining self-replication of a free-living organism – albeit one that grows relatively slowly and that requires fairly complex nutritional support. Significant work is required to develop an industrially useful chassis cell using this technology, including improved growth rate and the ability to grow well under stresses typical of an industrial bioprocess (Vickers, 2016). However, it does demonstrate proof of concept for extreme genome minimization – one of the two approaches to construct a chassis cell. The other is greenfield genome design, a considerably more challenging approach requiring both the capacity to synthesize complete genomes and a full understanding of minimal metabolic requirements. While writing DNA has notably lagged behind reading DNA, we are now at the stage where, with a reasonable amount of resources and infrastructure, one can write entire microbial genomes from templates. However, of the 473 genes encoded on the minimal genome, the function of 149 is currently unknown (Hutchison et al., 2016) – indicating that we still have some way to go to achieve the sufficiently detailed understanding of cellular requirements that would enable true greenfield design. Notwithstanding this, it is fair to say that we are starting to move towards the point where we can seriously consider the ground-up construction of chassis cells. This will be accelerated by the ability to interrogate in detail what it takes to make a functional genome through the kind of genome minimization experiments pioneered at JVCI.” (bold added)

Metaphor interpretation

Now for my naïve interpretation, and I might of course be totally wrong:

On the back of their 2010 success in synthesising Mycoplasma mycoides (JCV-syn1.0), Craig Venter and his team at the Craig Venter Institute published an article in March 2016 on how they designed and built a minimal genome, in this case JCV-syn3.0. This involved, I believe, taking a known bacterial species and deleting genes until they could delete no more, thus finding the smallest set of essential genes for that species which are fundamental to survival only, i.e. there are no luxuries, so to speak (for a more detailed description of this process, see here).

One can imagine using a similar process or a similar framework to build synthetic species to do industrial work, as having a smaller genome is easier to work with and there are fewer things that can interact unpredictably with our new introduced genes. However, there are still a lot of things we don’t know, as Venter and Vickers noted themselves, as for example finding that unexpected genes of unknown function are essential, even for a slow growing high maintenance strain. We also don’t know how protein folding works and so on and so forth.

But now to the metaphor: It was created to mark a contrast in minimal genome design between the new (greenfield) approach and the old (Venter) approach. Basically, the Venter approach is based on taking old stuff and reworking it (perhaps, in analogy to the ‘greenfield’ approach this can now be called the ‘brownfield’ approach), whereas the Vickers approach is to build a minimal genome from the ground up (the so-called ‘greenfield’ approach). One could also call this perhaps synthesis by reduction vs synthesis by construction…

Being able to build minimal genomes ‘from scratch’ would be really useful, as scientists would have much more control over their ‘creations’. It’s also interesting to note that the ‘writing’ metaphor is also used here, as in ‘writing minimal genomes from templates’.

And finally, a little bit of history. In another article published in 2016, Claudia Vickers provides a very good overview of ‘rational genome design’ (a new methodology for finding the optimal DNA sequences that confer new functions to a target organism), an older term/process that precedes and is linked to ‘greenfield genome design’ in various ways…. More to explore here…

Metaphor discussion

All metaphors carry conceptual baggage and all metaphors only work in some respects and not in others (think about the Rutherford model/metaphor of the atom as a solar system for example, or Newton’s view of the universe as a clockwork). Taking this into account, the question now is, does the ‘greenfield’ metaphor work and if so how?

Brownfield and greenfield sites are both sites on which one builds new buildings. Does this mean the buildings are different? What does this mean for the difference between what one may call the Venter and the Vickers types of genome design? Is it perhaps a difference between modifying or remodelling existing buildings on the one hand and building a new building ‘from scratch’ on the other, rather than between the sites on which they are built? If it’s the buildings rather than the sites we are focusing on, would a different metaphor work better, e.g. ‘clean sheet’ or indeed ‘clean slate genome design’?

If we accept the greenfield/brownfield distinction, a further question can be asked: Are we ready to leave brownfield approaches, whatever they are, behind and engage in greenfield approaches, at least as an aspiration – not only for synthetic biology, but also for green chemistry?

What do people think?

This is a creative metaphor that can stimulate thinking. Let’s talk about it!